The hazards posed to health by excessive exposure to lead are well documented In children, exposure to lead can cause growth deficiencies, loss of intelligence, hyperactivity and other serious problems. These matters are well documented in the medical literature. Lead is also well known to be toxic to adults.
Lead toxicity remains a substantial health problem, despite recent efforts to reduce the amount of lead in the environment, particularly in the United States, by use of low-lead gasolines and otherwise. The treatments which are available to remove lead from the body are relatively complex and expensive. Accordingly a rapid, reliable and definitive test for determining which patients require in-hospital treatment is important.
More particularly, it is currently estimated by the Federal Centers for Disease Control (CDC) that between 2 and 3 million children in the United States may suffer from lead toxicity. "Lead toxicity" is currently defined by the CDC as either (a) a blood lead content above 55 micrograms per deciliter of whole blood, associated with an "elevated" erythrocyte protoporphyrin (EP) concentration of 35 micrograms/deciliter or greater, or (b) an "elevated" blood lead level of 25-55 micrograms/deciliter, together with an elevated EP level, again of 35 micrograms/deciliter.
In case (a) above, treatment using a calcium disodium (CaNa.sub.2) EDTA chelator is normally initiated immediately upon detection of lead toxicity as thus defined, that is, simply responsive to the results of a blood test.
In case (b), a further soft tissue and skeletal lead burden test involving an EDTA chelator, discussed in detail below, is normally performed. Based on the results of this latter test, similar treatment may be initiated.
The blood lead test reflects recent exposure only, and only measures lead concentration in blood. Indices of adverse effects of lead on humans have also been recognized at blood lead levels below 25 micrograms/deciliter. The EP test is an index of lead toxicity on hemoglobin. Blood lead level--not EP values--primarily determines the sequence of diagnostic testing and subsequent treatment.
As indicated, both blood lead and EP tests are generally considered to reflect recent exposure to lead, e.g., in the past 30-90 days. A more serious problem is posed to health by the total body burden of lead, that is, the lead absorbed into the patient's tissues over his entire lifetime. This can only accurately be measured by direct evaluation of the lead content of the skeleton, in which a known proportion of the total lead absorbed by the body accumulates over time.
As indicated, a blood lead concentration in the 25 to 55 microgram/deciliter range is considered by the CDC to be "elevated". It is estimated that 2-3 million preschool children in the United States have blood lead levels in this range. Clearly, it is desirable to identify those having higher total lead burdens, so that they can be treated promptly, and so that treatment resources can be allocated efficiently and equitably. At present, the 25-55 microgram per deciliter range of blood lead contents is considered to be an inconclusive indicator of the necessity for treatment for lead toxicity, even when an "elevated" lead result is obtained. Accordingly, a further test, which accurately indicates the soft tissue and skeletal lead burden, is called for in these cases.
The current test for determining which children require treatment for lead toxicity is an "EDTA provocative" test, referred to herein as the "EDTA chelation" test. This test involves administering a painful injection of a chelating agent, the calcium disodium salt of ethylene diamine tetracetic acid (EDTA), which causes lead to be removed from the extracellular fluid and secondarily from bone and soft tissues and excreted. Performance of the test requires that all of the urine of the child be collected for a period of at least eight hours and in some cases up to 24 hours, so that the child must be monitored completely during that time. This is a relatively onerous test requirement, and the test is currently only available in a few hospitals and other medical facilities in the United States. Obviously, it is impractical to test millions of children by this cumbersome technique.
The present invention provides an improved test which is anticipated to obviate the present EDTA chelation test for most children, and which furthermore is responsive only to lead stored in bone.
Applicants and others have published a number of papers discussing the possibility of measuring skeletal lead burden in humans using x-ray fluorescence methods. Such techniques are used throughout science and industry. Broadly, in x-ray fluorescence analysis, a target of interest is irradiated by x-rays from a suitable source. Atoms in the target area absorb the x-rays and emit photons at a lower frequency, that is, fluoresce. The energies of the emitted photons are uniquely characteristic of the fluorescing atoms. The energy spectrum of the emitted photons can be analyzed using conventional instrumentation and used to determine the presence and relative amounts of the atoms making up the matter in the target area.
The present invention relates to improvements in methods and apparatus for performing such in vivo x-ray fluorescence tests to determine human skeletal lead burden and to methods of diagnosis and treatment based thereon.
For example, in "Feasibility of Non-Invasive Analysis of Lead in the Human Tibia by Soft X-ray Fluorescence," Med. Phys. 10(2), March/April 1983, pages 248-251, (the "1983 paper" hereinafter), applicants (with others) discuss a study assessing the feasibility of measuring bone lead by x-ray fluorescence as outlined above. In that study, a radioactive iodine source (.sup.125 I) was used as a source of "soft" x-rays, that is, low energy x-rays of 27.47 and 30.99 keV, which were used to irradiate the tibial cortex of the legs of six adults, post mortem. The results obtained by spectrum analysis of fluorescent photons correlated well to lead concentrations measured subsequently by flameless atomic absorption spectroscopy.
The 1983 paper suggests that use of relatively low energy soft x-rays to excite fluorescence would improve the safety of in vivo x-ray fluorescence lead measurements as compared to similar tests using higher energy hard x-rays (shown in, for example, Ahlgren et al., Phys. Med. Biol. 24, 136(1979)). The relatively low energy of the soft x-rays (approximately 10-30 keV) prevents them from penetrating deeply into the body tissues or from scattering beyond the body. This improves the safety of in vivo testing. Since the soft x-rays do not penetrate deeply into the body tissues, the bone to be thus examined must be near the surface of the patient's skin. Accordingly, the superficial tibial cortex, which is normally quite close to the surface, was explored. In the 1983 paper, the thickness of the overlying tissue was measured ultrasonically.
Applicants have subsequently measured the absorption of such soft x-rays in the soft tissue overlying the tibia and have developed a mathematical correction for the thickness of the overlying tissues on the absorption of the x-rays. See Wielopolski et al., "In Vivo Bone Lead Measurements; a Rapid Monitoring Method for Cumulative Lead Exposure", American Journal of Industrial Medicine 9, 221-226, 1986.
In the 1983 paper referred to above, applicants discuss the possibility of using an "x-ray machine" rather than a radioactive element, as follows:
If an x-ray machine rather than a .sup.125 I source were used to excite XRF [x-ray fluorescence], one could optimize the sensitivity of the system to detect lead, strontium or zinc in bone by varying the energy of the incident radiation. An --ray machine could also provide a sufficiently intense beam so that the polarization technique could be utilized. A polarized beam reduces the background and therefore improves the overall signal-to-noise ratio. PA0 A different source .sup.109 Cd which emits silver x-rays, can also be used for the fluorescence analysis of lead. It was found that with .sup.109 Cd the advantage of an increased photo electric cross-section in lead at the lower energies is offset by a lower conversion factor from x-ray flux to dose at these energies. One leg was analyzed with the .sup.109 Cd source . . . At present, there appears to be no clear advantage of one source over the other. (page 251).